carubicin and Leukemia-P388

It has been reported that KRN8602 shows antitumor effects similar or superior to those of Adriamycin (ADM) against several murine and human cell lines and has been found to be effective against multidrug resistant tumor cells. We investigated the pharmacokinetics of KRN8602, a new morpholino anthracycline, in comparison with ADM in mice bearing colon26 adenocarcinoma. After intravenous administration, both drugs disappeared triexponentially from the plasma and KRN8602 was eliminated faster than ADM. The rate of elimination of KRN8602 from tissues was also faster than than of ADM. The relative order of the area under the curve (AUC) of KRN8602 was spleen > tumor > small intestine > lung > kidney > heart > liver > brain > plasma, while that of ADM was spleen > kidney > lung > liver > heart > small intestine > tumor > plasma. ADM was not detectable in the brain. The AUC of KRN8602 was higher than that of ADM in the tumor and brain, but it was lower in other tissues. The tissue-to-plasma concentration ratio (KPapp) of KRN8602 was higher than that of ADM in the tumor, spleen, small intestine and brain. KRN8602 was metabolized to several metabolites. The concentrations of M1 and M2 (glycoside-type metabolites) was relatively high in the spleen. M3 (aglycone-type metabolite) showed a very high AUC ratio in the liver (34%). In tumor, M1 and M2 concentrations were low and M3 was not detected. KRN8602 had a greater activity than ADM and M2 had a cytotoxic activity similar to KRN8602 against colon26 cells in an MTT assay. These results suggest that the strong antitumor effect of KRN8602 against colon26 is due not only to its strong cytotoxic activity but also to its marked transferability into tumors. KRN8602 shows better selective toxicity than ADM, because KRN8602 is more selective for tumors than ADM and less is transferred to normal tissues.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Brain Chemistry; Carubicin; Cell Survival; Chromatography, High Pressure Liquid; Colonic Neoplasms; Doxorubicin; Female; Intestine, Small; Kidney; Leukemia P388; Liver; Lung; Mice; Myocardium; Neoplasm Transplantation; Spleen; Tissue Distribution; Tumor Cells, Cultured

Toxicity and antitumor activity of five derivatives of rubomycin and carminomycin were studied in animals. The derivatives were prepared by modification of the methyl C-14 group. These were the following: 14-chlorrubomycin, 14-chlorcarminomycin, 14-salicyloyloxyrubomycin, 14-salicyloyloxycarminomycin and 14-quinaldinoyloxyrubomycin. The chemotherapeutic study revealed that, in their activity, all the compounds were inferior to the starting antibiotics. Unlike the other derivatives, 14-chlorcarminomycin induced a significant inhibition of leukemia P-388 development (the average lifespan of the mice amounted to 165 per cent as compared to the control). However, in the magnitude of its effect, the derivative was inferior to carminomycin.

Topics: Animals; Carubicin; Daunorubicin; Drug Evaluation, Preclinical; Female; Leukemia P388; Leukemia, Experimental; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasms, Experimental

3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), a morpholino anthracycline derived from 13-deoxo-10-hydroxycarminomycin (R20X2) was 16 times less cytotoxic than R20X2 against cultured P388 leukemia cells. The reduced cytotoxicity of MX2 was not explainable by intracellular or intranuclear concentration of the drug or by its DNA-intercalating activity. Binding of MX2 and R20X2 to DNA was measured, after isolating the DNA fraction from an incubation mixture of the drugs with P388 cells or with calf thymus DNA. The amount of R20X2 bound to the DNA was obviously larger than that of MX2, and was dependent on incubation time. These data suggest that the poor binding activity of MX2 to DNA contributes to its reduced cytotoxicity.

Topics: Animals; Carubicin; Cells, Cultured; Daunorubicin; DNA, Neoplasm; Leukemia P388; Leukemia, Experimental; Rats; Structure-Activity Relationship

Topics: Animals; Anthracyclines; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Carubicin; Leukemia P388; Mice; Naphthacenes

The cytotoxic effect of (7S)- and (7R)-O-epoxyalkyl derivatives of daunomycinone on leukemia P388 cells was followed in in vitro tests and their mutagenicity was determined by means of the bacterial SOS chromotest. The biological effects of the substances were compared with those of daunomycin, carminomycin and nogalamycin. The most efficient derivative proved to be the (7S)-9-acetyl-4-methoxy 7-O-(2,3-epoxypropyl)-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5, 12-naphthacenequinone 10 which inhibited the DNA and RNA synthesis and proliferation of P388 cells on the level of daunomycin or carminomycin. The cytotoxic and mutagenic action of 7-O-epoxyalkyl derivatives of daunomycinone was affected by the length of alkyl and its configuration.

Topics: Animals; Carubicin; Cell Survival; Daunorubicin; DNA Replication; Leukemia P388; Mice; Mutagenicity Tests; Naphthacenes; Nogalamycin; RNA; Structure-Activity Relationship

Fe(III) complex of an antitumoral antibiotic carminomycin has been studied. Using potentiometric and spectroscopic measurements we have shown that carminomycin forms with Fe(III) a well-defined species in which three molecules of drug are chelated to one Fe(III) ion. This occurs with the release of one proton per molecule of drug. Magnetic susceptibility measurements suggest that six oxygen atoms are bound to iron. The stability constant is 3 X 10(34). The in vitro inhibition of P 388 leukemia cell growth by this complex compares with that of the free drug. This complex, unlike the free drug, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.

Topics: Animals; Carubicin; Cell Division; Circular Dichroism; Cytochrome c Group; Cytochrome Reductases; Daunorubicin; Drug Stability; Horses; Hydrogen-Ion Concentration; Iron; Leukemia P388; Mice; Myocardium; NADH Dehydrogenase; Organometallic Compounds; Potentiometry; Spectrophotometry; Superoxides

A comparative quantitative investigation of colony-forming ability of mouse bone marrow hemopoietic stem cells in the case of ordinary leukemia variant (P-388) and carminomycin-resistant variant (P-388/k) was carried out. Leukemia bearing mice received single injections of increasing doses of carminomycin on the 5th day after transplantation and 24 hours later the bone marrow was investigated for quantity of colony-forming units in the spleen (CFUs). Dynamics investigation of bone marrow cells in the case of P-388 and P-388/k (without treatment) reveals the common tendency to a decrease of these cells in the period before animal death. Sensitivity of colony forming cells (CFUs) to different doses of the antibiotic of mouse bone marrow in both cases (P-388 and P-388/k) was practically the same. Dynamics of CFUs in two populations of cells after a single injection of carminomycin in doses causing the killing of 50% of CFUs showed that the antibiotic inhibited CFUs equally (50%). However this inhibition in case of CFUs with P-388/k leukemia was almost five times longer than in the case of ordinary P-388 one. Based on the investigations conducted the second injection of the antibiotic to mice with P-388/k leukemia on the fifteenth day after the first one may be recommended.

Topics: Animals; Bone Marrow; Carubicin; Colony-Forming Units Assay; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Female; Hematopoietic Stem Cells; Leukemia P388; Mice; Mice, Inbred Strains; Neoplasm Transplantation

The carminomycin-resistant strain (P-388/c) of P-388 lymphoid leukemia is obtained. Resistance development is accompanied by higher sensitivity to cytostatics, rise of hyperploidy, replacement of the stem line, presence of definite markers in leukemic cells as well as by the appearance of a clone of cells with higher dry mass. At the level of CFUs after the carminomycin administration more remote terms of cell restoration than in case of P-388/c lymphoid leukemia are determined. The P-388/c lymphoid leukemia cells lost their sensitivity to carminomycin at the stage of the DNA synthesis. Accumulation of cells is observed in phase G2 of the mitotic cycle.

Topics: Animals; Antineoplastic Agents; Carubicin; Cell Survival; Daunorubicin; Drug Resistance; Female; Hematopoietic Stem Cells; Leukemia P388; Leukemia, Experimental; Mice; Mitosis; Neoplasm Transplantation

Effects of carminomycin on the colony-forming ability of bone marrow haemopoietic stem cells (CFUs) were compared in normal mice with steady state and actively regenerating bone marrow, and in P-388 and La leukemia-bearing mice. CFUs assays were performed 24 h after treatment of donor mice with the increasing doses of the drug. Leukemia-bearing mice received carminomycin on the 5th day after transplantation. The dose-effect curves were exponential for CFUS normal mice with both the steady state and active proliferation state of bone marrow. The maximal effect was found 24 h after injection of 0.7 mg/kg of carminomycin (ED50 for CFUS) being more pronounced in regenerating bone marrow. The dose-effect curves for leukemias were also exponential. In the case of La leukemia the killing of CFUs by carminomycin was the highest as compared with P-388 leukemia.

Topics: Animals; Carubicin; Colony-Forming Units Assay; Daunorubicin; Female; Hematopoietic Stem Cells; Leukemia P388; Leukemia, Experimental; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Rats

A new antibiotic complex has been obtained from the cultures of an actinomycete, strain FA-1180, isolated from a soil sample collected at lake side of Biwa in Japan. On the basis of taxonomic studies the producing microorganism is designated as Actinomadura roseoviolacea var. biwakoensis nov. var. The antibiotic complex belongs to the class of anthracycline glycoside antibiotics. All components form deep red fine needles on crystallization; components are named rubeomycin A, A1, B and B1. These components exhibit activity against Gram-positive bacteria as well as Yoshida sarcoma cell in vitro. These components are also effective on P388 leukemia.

Topics: Animals; Anthracyclines; Anti-Bacterial Agents; Bacteria; Carubicin; Leukemia P388; Mice; Nocardiaceae